PROJECT SUMMARY For resource-limited settings, the World Health Organization recommends that HIV infected pregnant women who do not need treatment for their own health receive zidovudine (ZDV) from 28 weeks' gestation, with single dose nevirapine (NVP) at onset of labor and in infants at 48-72 hours of life for the prevention of mother to child transmission (PMTCT) of HIV. This regimen is safe and reduces the risk of transmission to ?2%, but it is associated with the selection of NVP resistance mutations in mothers and infected children. These mutations have been shown to diminish the efficacy of subsequent NVP based therapies. In industrialized countries, more complex regimens using highly active antiretroviral therapy (HAART) combinations during pregnancy also achieve very low transmission rates while avoiding the selection of resistance mutations to NVP. The study will compare in a multicenter, phase III, randomized controlled, clinical trial the efficacy, safety, and feasibility of a simple, affordable and potent combination of ZDV + lopinavir/ritonavir (LPV/r) from 28 weeks' gestation versus the regimen currently recommended by WHO in a non breastfeeding population. The specific objectives are to evaluate and compare between the two approaches: (1) the risk of HIV transmission (infant HIV status by DNA-PCR); (2) the incidence of clinically significant adverse events in women and infants, and the CD4 and viral load evolution in women; (3) the incidence of HIV resistance mutations. The pharmacokinetics of LPV/r in Thai pregnant women will also be assessed. If proved to be as efficacious and safe as the current WHO regimen for PMTCT, this regimen will provide an option to maintain a low risk of perinatal transmission and resolve the dilemma posed by NVP resistance mutations for both mothers and infected children, thereby preserving their future treatment options. The study will add a third arm to an NIH funded clinical trial, which evaluates another strategy to resolve the problem of NVP resistance mutations, i.e. ZDV from 28 weeks' gestation and infant only NVP compared to the WHO regimen (R01 HD 052461). This three arm clinical trial will follow 2097 consenting HIV-1 infected pregnant women with CD4 count >250/mm3 and their infants in a network of 43 Thai public hospitals up to 24 months after delivery (n=699 per arm including 5% non evaluable; alpha 5%; power: 80%; delta for non-inferiority testing: 1.5%).